DESCRIPTION (Adapted from the Candidate's Abstract) Women who inherit a mutation in the BRCA1 or BRCA2 breast cancer susceptibility genes have an 80-90% lifetime chance of developing breast and ovarian cancer. Current medical practice encourages these predisposed individuals to begin frequent mammographic screening as early as 20 years of age. Unfortunately, these women will have a much greater life time exposure to low-level radiation as well as other environmental agents which may increase the risk for breast cancer development. Thus, we need to understand gene environment and gene-gene interactions that affect breast cancer risks resulting from exposure to radiation and other environmental agents in BRCA2 mutation carriers. Balb/c and SWR mice are highly susceptible to radiation- induced mammary carcinogenesis relative to other inbred strains such as C57BL/6 mice. It is hypothesized that mice harboring a BRCA2 mutation on the Balb/c and SWR genetic backgrounds will be more susceptible to mammary carcinogenesis than their wild-type littermates. The specific aims are to: 1) determine if radiation exposure increases the risk of mammary carcinogenesis in BRCA2-deficient mice; 2) evaluate the SWR genetic background for its ability to modify mammary tumor induction in BRCA2-deficient and wild- type Balb/c mice; 3) assess high dose radiation-induced mammary tumorigenesis by a mammary gland transplantation technique using BRCA2-deficient and wild- type mice; and 4) examine high dose-radiation sensitivity at tissue sites associated with human BRCA2 mutations. From these studies, the candidate will be able to (a) enhance our understanding of the role of BRCA2 mutations of radiation-induced mammary carcinogenesis, (b) evaluate the effect of genetic background on susceptibility to breast cancer, and (c) provide insights into the risk for other types of cancer that may be associated with BRCA2 mutations. Increased cancer risks from radiation exposure in BRCA2-deficient mice could have important implications for diagnostic procedures such as mammography in genetically predisposed women and these BRCA2-deficient mice may provide a useful alternative bioassay for human breast carcinogens.